11-substituted-desa-pregnanes and derivatives thereof

ABSTRACT

THIS INVENTION IS DIRECTED TO 11-SUBSTITUTED-DES A-PREGNANES AND DERIVATIVES THEREOF WHICH ARE USEFUL AS INTERMEDIATES IN THE PRODUCTION OF 9B, 10A-KNOWN STEROIDS OF THE PREGNANE SERIES. THESE LATTER COMPOUNDS CAN BE UTILIZED A PROGESTATIONAL AND SALT-RETAINING AGENTS.

United States Patent Olfice Patented Aug. 20, 1974 ABSTRACT OF THE DISCLOSURE This invention is directed to ll-substituted-desA-pregnanes and derivatives thereof which are useful as intermediates in the production of 9fi,l0a-known steroids of the pregnane series. These latter compounds can be utilized as progestational and salt-retaining agents.

RELATED APPLICATIONS This application is a division of applicants co-pending application Ser. No. 736,569, filed June 13, 1968, now abandoned, which in turn is a division of applicants copending application Ser. No. 499,094, filed Oct. 20, 1965, now US. Pat. 3,574,761, being a continuation-in-part of applicants co-pending application Ser. No. 400,206, fi-led Sept. 29, 1964, now US Pat. 3,412,107.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids. Natural steroids possess a 9a,105-stereochemical configuration. Steroidal compounds possessing the unnatural 9,8, loot-configuration represent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be obtained by totally classical chemical means. In fact, the only known methods for obtaining steroids possessing the unnatural 95,100:- configuration involve at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefficient and give only small yields.

It is an object of the present invention to provide intermediates and processes which enable the preparation of 9/3,10a-steroids without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide novel intermediates and processes which will enable the further exploration of steroids having the unnatural 9fi,10a-configuration. It is also an object of this invention to provide novel 9;8,10u-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e. involving no photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 95,10a-c0nfigurati0n.

In one aspect, the novel intermediates and processes of this invention enable the preparation of 9p,10a-steroids of the androstane series of the formula wherein R is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen or lower alkyl and R and R taken together, are selected from the group consisting of (Up-OH, 17a-lower alkanoic acid lactone) and 0x0; R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the 6- or 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen.

Compounds of formula I are useful as anabolic agents.

Other 9fi,10a-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae wherein R R Y and X have the same meaning as above. Compounds of formula III are useful as progestational agents and compounds of formula II are useful as antiandrogenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention enable the preparation of 9fl,10a-steroids of the 17,6-pregnane series of the formula wherein Y and X have the same meaning as above; R;, is selected from the group consisting of hydrogen, lower alkyl, fluoro, hydroxy and lower alkanoyloxy; R is selected from the group consisting of hydrogen and halogen; and R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and halogen.

Compounds of formula IV are useful as progestational agents.

Other 9fi,l0u-steroids of the l7 8-pregnane series, preparable from the novel compounds and process of this invention, are of the formula GHzOH wherein -R' R Y and X have the same meaning as above.

Compounds of formula V are useful as salt-retaining agents, i.e. are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy, acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine.

The expression (17 3-OH, 17a-lower alkanoic acid lactone) refers to a configuration on the C-17 carbon atom illustrated as follows:

ll 0-0 ml wherein W is lower alkylene, e.g. polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in '6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 9,8,10a-androstanes of formulae I-III and of 9B,l0a-l7fi-pregnanes offormula'e IV-V which comprises the hydrogenation of desA-androst-9-en-5-ones or of desA-l7B-pregn-9-en-5-ones to 9fl,l0a-desA-andro stan-S-ones or 9B,IOB-desa-17,3-pregnan-5-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl or ethyl vinyl ketone preferred (as well as substitutes therefor such as l-tcrtiary amino-3- 4 butanone, l-tertiary amino-3-pentanone and quaternary ammonium salts thereof), l-Q-butan-3-one, l-Q-butan-3- one lower alkylene ketal, 1-Q-butan-3-ol, esterified l-Q- butan-3-ol, 1-Q-butan3-0l ether, 1,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, 1-pentan-3-one, 1-Q-pentan-3-one lower alykylene ketal, l-Qpentan-3-ol, esterified l-Q- pentan-3-ol or 1-Q-pentan-3-ol ether, which condensation yields the desired 9/3,10a-steroids. The symbol Q is bromine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA-androst-9-en-5- one or desA-17B-pregn-9-en-5-one starting materials from natural steroids. 1

In one embodiment, a steroid of the 3-oxo-androst-4- ene or 3-oxo-l7 3-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5-oxo-3,5- seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A- nor-17fi-pregnan-3-oic acid, which 3-oic acid can then be converted to a mixture of a 10a-desA-androstan-5-one and a IOfl-desA-androstan-S-one or a mixture of a IOa-desA- l7 3-pregnan-5-one and a 10 8-desA-17/3-pregnan-S-one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5-en-3- one or a 4-oxo-17,6-pregn-5-en-3-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted into the desired desA-compound. The desA-compound can then be converted into the startin material desA-androst-9-en-5-one or desA-17p-pregn- 9-en-5-one via a two-step sequence of halogenation and dehydrohalogenation. 1

In another embodiment of this invention, desA-androst- 9-en-5-one or desA-17,8-pregn-9-en-5-one starting materials can be prepared from ll-hydroxy steroids of the 3- oxo-androst-4-ene or 3-oXo-17B-pregn-4-ene series. This can be effected in a variety of ways. In one approach, an ll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or 3-oxo-17fl-pregn-4-ene series is converted into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed ll-(esterified hydroxy)-containing compound yields of the corresponding ll-(esterified hydroxy)- 5-oxo-3,S-seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy)-5-oxo-3,5-seco A nor-17,8-pregnan-3-oic acid which upon pyrolysis of a salt of said 3-oic acid yields the desired desA-androst-9-en-5-one or desA-17,8-pregn-9- en-S-one starting material. i

A further approach involves formation of an 11-.hydroxy desA androstan-S-one or ll-hydroxy-desA-17dpregnan-S-one from an ll-hydroxy steroid of the 3-oxoandrost-4-ene or 3-oxo-17fl-pregn-4-ene series via an oxidative ring opening of the A-ring of said ll-hydroxy steroid which yields an 11-hydroXy-5-oxo-A-nor-3,5-secoandrostan-3-oic acid 3,1l-lactone or an ll-hydroxy-S-oxd 3,5-seco-17/3-pregnan-3-oic acid 3,11-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the ll-hydroxy-desA- androstan-S-one or 1l-hydroxy-desA-l7 8-pregnan-i-one. Esterification of the ll-hydroxy moiety of the so-obtained compound with an acid moiety yields an ll-(esterified hydroxy)-desA-androstan-5-one or an ll-(esterified hydroxy)-desA-l7fi-pregnan-5-one which upon elimination of the leaving group (i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-l7,8- pregn-9-en-5-one starting material. Though, in the above reaction sequence either llu-OH or llfl-OH starting material steroids can be used, it is preferred to use lloi-OH starting materials.

As will be appreciated from the above discussion, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of sub stituents found in the 16- and/or 17-position of the starting material natural steroids. However, in order to obtain unnatural 9,3,l0a-steroids0f formulae IV, it is necessary or desirable to pr tect certain of the 16- and/or 17-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of formulae I-V possessing the unnatural 9,8,l0a-configuration is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means known pre se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are exemplified by the 16- hydroxy group in a compound of formulas I-V, the 175- hydroxy group in a compound of any of formulas I-III, the 17a-hydroxy or -oxo group in a compound of any of formulas IV-V, the 21-hydroxy group of a compound of formula V or the 17-oxo group of a compound of formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalizatiou, i.e., by reaction with a lower alkanediol, to yield a l7-lower alkylene dioxy or 20-lower alkyleue dioxy compound, i.e., a 17-ketal or a 20-ketal.

The 16-hydroxy, l7u-hydroxy, 17/3-hydroxy or 21-hydroxy moieties can be protected by esterification and/ or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g. acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the 16x-hydroxy, l7u-hydroxy, or 21-hydroxy substituent can be elfected by forming the lower alkyl ortho ester thereof, i.e. 160:,17ozor 17a, 21-lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benzyldryl and trityl ethers, or a-lower alkoxylower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

In compounds containing the dihydroxyacetone side chain at C-l7 (for example, compounds of formula V wherein R is hydroxy), the side chain at C-l7 can be protected by forming the l7,20;20,2l-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,2l-diesters. The 17,21-acetal or ketal and 17,2l-diester hinder the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,20;20,2l-bis-methylenedioxy derivatives actually convert the ketone to a non-reactive derivative. When both a 16a-hydroxy and 17a-hY- droxy substituent are present, these groups can be protected via formation of a 16a,17a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 170:- hydroxy nor 21-hydroxy substituent but there is present a 20-oxo group, the 20-oxo' group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the l7-acetyl side chain can be protected via conversion to a 17-(a-hydroxyethyl)-side chain. Regeneration of the l7-acetyl side chain can be simply efiected via'conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in compounds containing a 17-oxo, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the 17-oxo group can be reduced to a 1713-01-1, 17a-H moiety, from which, when desired, the 17-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a 20-hydroxy or U a-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The l6ot-17nz or l7a,2l-acetals and ketals above discussed can be formed by reacting l6a,17a-bis-hydroxy or l7a,2l-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanols of at least two carbon atoms, such as paraldehyde, propanol and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanols), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1,1,Ltrifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)-benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, B- phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, u,a,a-trifiuoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. pchloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di(lower alkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone'; benzophenone, and monoor bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl 3 butanone and 1-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the 16a,17aor l7a,21-bis-hydroxy grouping form an acetal or ketal group of the formula sisting of hydrogen and lower alkyl; Q is individually selected from the group consisting of lower alkyl and aryl; and P and Q taken together are lower alkyleue.

The term lower alkylene comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of formulas I through V are prepared from 9/3-l0 8-desA- androstan-S-ones or 9/3,10p-desA-pregnan-5-ones of the formula wherein X has the same meaning as above and D represents the carbon and hydrogen atoms necessary to complete the steroid D-ring, as well as the atoms in the substituents in the 16- and 17-positions, as defined in formulae I-V above.

Thus, 9,8,10/8-androstanes of formula I can be prepared from 9,8,10,3-desA-androstan--ones of the formula X VII wherein R R R and X have the same meaning as above.

Similarly, 9/i,10a-androstanes of formula I can be prepared from 9B,10fi-desA-androstan-S-ones of formula VIII and 9p,10u-androstanes of formula III from 9,3,10fl-desA- androstan-S-ones of formula IX.

k-lower alkenyl H3O j H X VIII R30 R! --lower alkynyl M H 1130 N 1 H 0 X IX wherein R R and have the same meaning as above. Moreover, 9fi,l0a-l7}3-pregnanes of formulae IV and wherein R' R R and X have the same meaning as above.

The conversion of a 9,8,l0fl-desA-compound of formula VI to a 95,10a-steroid of formulae I-V (i.e., VII- 1, VIII- II, IX III, X IV and XI V) is effected by condensing the 95,10B-desA-compound with a compound selected from the group consisting of lower alkyl vinyl ketone (as well as substitutes therefor such as l-tertiary amino-3-butanone, l-tertiary amino 3 pentanone and quarternary ammonium salts thereof), 1,3-dichlorobut-2- ene, 1,3 dichloropent 2 ene, 1-Q-butan-3-one, l-Q- butan 3 one lower alkylene ketal, 1-Q-butan-3-ol, 1- Q-butan 3 o1 ether, esterified 1-Q-butan-3-ol, l-Q- pentan 3 one, l-Q-pentan 3 one lower alkylene ketal, l-Q-pentan 3 ol, l-Q-pentan 3 ol ether or esterified 1-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two being preferred. Methyl vinyl ketone and 1- tertiary amino 3 butanone are the preferred reagents, and the former is especially preferred. Prior to the condensation it is desirable to protect the 20-keto group present in compounds of formulae X and XI, then it is not necessary to protect l6u,l7a or 21-hydroxy groups which are present, but groups protecting these moieties can be retained through the condensation reaction.

The above indicated substitutes for lower alkyl vinyl ketones are compounds wherein the vinyl moiety is replaced by a moiety of the formula wherein each R is lower alkyl or taken together both Rs are lower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moieties are, for example, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. The quaternary ammonium salts thereof are formed via the utilization of conventional quaternizing agents, for example, lower alkyl or phenyl-lower alkyl (especially benzyl) halides, mesylates or tosylates.

When a lower alkyl vinylketone or substitute therefor, l-Q-butan-3-one or l-Q-pentan-B-one is used as the reaction partner for the condensation, ring closure to ring A (containing a 3-oxo moiety) of the desired 913,10a-steroid of formulae -IV occurs simultaneously with the condensation. However, when 1,3-dichlorobut-2-ene, 1,3-dichloropent-Z-ene, l-Q-butan-3-one lower alkylene ketal, l-Q- 9"; butan-3 -ol, 1-Q-butan-3-ol ether, esterified 1-Q-butan-3-ol,

l-Q-pentan-S-one lower alkyleneketal, 1-Q-pentan-3-ol,.

1-Q-pentan-3-ol ether,-or esterified l-Q-pentan-3-ol is used as the 'reactionpartner, a subsequent step to generate the 3-oxomoiety is required. When-.l-Q-butan-3-ol or l-Q- pentarr-, 3-ol is used as the reaction partner, the x0 moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se, for example, chromic acid, chromium trioxidejn acetic acid or the like. When esterified or etherified 1'-Q"-butan-3-ol or esterified or etherified 1-Q-pentan-3-olis used as the reaction partner, hydrolysis of the v esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting"such l Q-butan 3-ol 'or"'l'-Q-pentan-3-ol esters is suitably conducted"'by"alkaline hydrolysis, e.g., 'via the use of an "aqueous metal hydroxide such as aqueous sodium hydroxide. "Suitable ethers are, for example, lower alkyl ethers, i.e. 3-rhethoxy, S-ethoxy or the like; 'and'the'se are suitably hydrolyzed by acid hydrolysis, e.gi'wia the use of an aqueous'm'in'eral acid such as hydrochloric acid, sulfuric acid-or "the like. When a l-Q- butan-3-one lower alkylene 'ketal" or a l-Q-pentan-S-one lower alkylene 'ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of'the 3-oxo moiety. Finally, when 1,3-dichlorobut-3-ene or 1,3-dichloropent-3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that 1,3-dichlorobut-2-ene and l,'3-dichloropent-2-ene may be used as reaction partners with compounds of formulae X and XI, but not with the l7a-lower alkyl, alkenyl or alkynyl compounds of formulae VIII-IX. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of formulae I-V wherein Y is hydrogen is obtained. Similarly, whna reaction partner based on pentane is utilized a compound of formulae I -V wherein Y is methyl isobtained.

vIn addition to the preparation of compounds of formulae I-V'from compounds 'of formulae VI-XI by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of formulae I-V which, in the A-ring, in addition to containing an 'urisaturation between the 4- and 5-positions also contain an' unsa'turation between the 1- and 2-positions."Such -l-,4-diene products corresponding to the compounds-of formulae I-V can be prepared from compounds of formula'e 'VL-XIby condensation of the latter with a reaction partner selected from the group consisting of ethinylmethyl ketone and ethinyl ethyl ketone (as well as substitute's 'therefor such as B-tertiary amino=vinyl""methylor ethyl ketone, quaternary ammonium -salts-ther'eof,"and ti-lower alkoxy-vinyl methyl or ethyl ketone);ondens'ationto prepare such as 1,4-diene productcor'responding tothe compounds of formulae I-V is effected under-the same conditions as is the condensation to prepare a-compound 'of formulae I-V. The soobtain'ed 1,4-dienes'are useful inthe 'same way as the correspondingly substituted"4 ene-compounds of formulae "The condensation'is suitably'effectedat, below or above roomtemperature. For-examplefalt thereflux tempera ture. of'the reaction medium or at icet'emperature (0 'C.) or below. Moreover, the condensatio'mis suitably effected in an organic medium. Preferably the solvent is a lower -alkanol, such as methanol, isopropanol, tert buta'nOI, eth-' anol, or another non keton'icorganic solvent; such 'as'an' ether, e.g. dioxane, .diethyl ether; diisopropyl ether, aro-' densation, and this can be effected via use of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium t-amylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are l-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and fitertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylamino groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary ,B-lower alkoxy vinyl methyl or ethyl ketone is ,B-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to 9B,lOB-desA-androstan-S-ones of formulae VII-IX or to 9B,IOfi-desA-pregnan-S-ones of formulae X-XI. Thus, 9,8,lOfl-desA-androstan-S-ones of formula VII can be prepared via hydrogenation of desA-androst-9-en-5-ones of the formulae 1 wherein R R R and X have the same meaning as above.

Also, 9 3,IOfi-desA-pregna-S-Ones of formulae X and XI can be prepared by'hydrogenation of desA-pregn-9- en-S-ones of the formulae v wherein R R R and X have the same meaning as above.

Prior to hydrogenation, the C-20 'keto group in compounds of formulae XV and XVI or -17 keto group in compounds of formula XII should be protected either by conversion to the corresponding carbinol or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting a hydrogen atom in each of the 9- and 10-posi'tions, can also simultaneously effect hydrogenation of other groups in the molecule. For example, the C20- keto group can be hydrogenated to the corresponding carbinol or the C-17 lower alkenyl group in compoundsof formula XIII or the C-17 lower alkynyl group in compounds of formula XIV can be hydrogenated to the corresponding C-17-lower alkyl compounds. Compounds of formulae VIII and 1X can, in turn, be prepared from compounds of formula VII wherein R and R together are oxo via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for example, by forming S-ketals without concurrent blocking of the 17-keto group. In the same manner compounds of formulae XIII and XIV can be formed from compounds of formula XII wherein R and R taken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of formulae XIIXIV and of desA-pregn-9-en-5-ones of formulae XV-XVI is one of the main features of this invention. It is elfected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example, rhodium on charcoal (or carbon powder, carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of formulae VII-XVI gives a substantial yield of a compound of formulae VI- XI. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the formulae VI-XI. This catalytic hydrogenation is suitably effected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Lower alkanols are preferred solvents. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid suchas a lower alkanoic acid, for example, acetic acid. The reaction can be conducted at, above or below room temperature, for example, from about --5 C. to about 100 C. However, it is preferably conducted at a temperature between about 0 C. and about 35 C.

As described above, the desA-androst-9-ene-5-ones or desA-17/8-pregn-9-en-5-ones.,of formulae XII-XVI can be prepared from natural steroids .by a variety of methods. Thus, in one embodiment of this invention said desA-androst-9-en-5-ones or desA-l7fl-pregn-9 en-5-ones can be prepared from steroids of the 3-oxo-androst-4-ene 12 or 3-oxo-17fl-pregn-4-ene series by a reaction sequence which involves as a first step an oxidative ring opening of ring A of the natural 'steroid.For"this oxidative ring opening there can be used as startingm'aterials, naturalsteroids of the 3-oxo-andros't-4-eiie'or3-oxo-l7;3-pregn 4-ene or 3-oxo-l7p-pregn-4 en'e series of the formula:

H3O I I a IX n;v wherein X is a substituent in the 6-po sition selected from: the group consisting of'hydrogen, lower alkyl, lower alkylthio and lower alkanoylthio or a substituent in the 7-posi-Q tion selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen, and Z represents the carbon and hydrogen atoms neces{ sary to complete the steroid -D-r ing, as well as the atoms in the substituents in the -16- and l7 -positions as defined in formulae 1, IV, and V above. a

The oxidative ring opening of a natural steroid of formula XVII yields a 5-oxor3,5-seco A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A-norpregnan-3-oic acid, of the formula I XVIII wherein X and Z have the same meaning asabove. f

The oxidative ring opening of the compound of formula XVII can be performed by a variety of methods, In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably. carried out in an, organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, .or the like, or .a mixture of two or more of such solvents such as ethyl acetate/acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the, ozonolysis is advantageously. con ducted at below room temperature. Thus, it'is preferably conducted at a temperature between about-+70"- C. and about 25 C. The resulting ozonidescan bedecomposed by conventional means, for example, by treatment .with water, hydrogen peroxide in :water, acetic -,acid or, ethyl acetate, or the like. Theoxidativer-ing openingof a compound of formula XVII ,toa compound of formula XVIII can also be effectedby other oxidation means, for example, by treatment with hydrogen-peroxide; It, should be noted that an oxidative, ring opening by either ozonoly-v sis or by treatment-with, hydrogen peroxide, does-not require protection of any. of; the substituents at C-16 or C-l7. However, as stated'above, it'maysbe desirable to protect these substituents'against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening canalso-be effected by oxidation with chromium 'trioxide-or via treat ment with sodium periodate andpotassium permanganate in potassium carbonate solution and if these oxidation means are used, it is necessary to protect-any secondary hydroxy groups which might be present'such as a 16,17 3- or Zl-hydroxy group; preferably, for the purpose of this reaction, with non-aromatic protecting-groups. ,1 .Following the oxidative. ring opening of-the'A-ring, the so-obtained 5-oxo-3,5-ser:orA-norandrostan-3 oic acid or 5-oxo-3,S-seco-A-norprqgnan-S-oic acid :of formula XVIII is converted into a mixture of a 10a-desA-andro- 13 stan-S-one or a mixture of a la-desA-pregnan-5-0ne and a IOfl-desA-pregnan-S-one as illustrated below:

XVIII alkali metal salt of XVIII "wherein in formulae XIX and XX, X and Z have the same meaning as above.

The compounds of formula XIX are lou-desA-androstan-5-ones or d-desA-pregnan-5-ones, depending on the meaning of Z, and the compounds of formula XX are 10 3 desA-andrOstan-S-Ones or 10fl-desA-pregnan-5-ones. The conversion of a compound of formula XVIII into the compounds of formulae XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of formula XVIII into a corresponding metal salt, forexample, an alkali metal salt such as the sodium orlithium salt. This conversion to a metal salt canbe effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable'embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200' C. to about 350 C'. in the presence of a proton acceptor, e.g. an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is 'a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is advantageous to conduct "pyrolysis is to heat, preferably'at atmospheric pressure, a

solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of formula XVIII in a basic organic solvent. The basic organic solvent should, of

-"-course,' be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200 C. and about 300 C., and preferably between about 230 C. and about 260 C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of formula XVIII to compounds of ysis in a sealed tube or an autoclave.

14 In another aspect, compounds of formula XIX can be prepared from compounds of the formula wherein X' and Z have the same meaning as above.

The compounds of formula XIX can be prepared from compounds of formula XDCA in the same manner that compounds of formula XIX are prepared from compounds of formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of formula XIXA followed by elimination of the residue of the A-ring, to yield a compound of formula XIX. The oxidative ring opening of the compound of XIXA can be performed by ozonolysis as described above for the conversion of a compound of formula XVII to a compound of formula XVIII. Such ozonolysis of a compound of formula XIXA yields a compound of the formula XIXB wherein X and Z have the same meaning as above, and A is carboxy or formyl.

A compound of formula XIXB can then be converted to a compound of formula XIX. This removal of the residue of the A-ring, i.e. decarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of formula XIX, but also a minor yield of the corresponding lOB-isomer of formula XX.

Compounds of formula XIX can also be formed from a compound of formula XVIII via the formation of an enol-lactone of a compound of formula XVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxo-pregn- 5-en-3-one of the formula:

wherein X and Z have the same meaning as above, which can then be reacted with a Grignard' reagent, such as phenyl magnesium bromide or phenyl lithium, to form the resulting aldol of, for example, the formula XXII - :wherein X and Zhave the same meaning as above, which,

upon treatment with'analkali metal hydroxide, such -.as potassium hydroxide, at an elevated temperature, for example, from about 200 C. to about 240 C., is converted to the corresponding la-desA-androstan-5-one or IOa-desA-pregnan-S-One of formula XIX.

It should be noted that though the pyrolysis of a compound of formula XVIII yields both the 10,8-compounds of formula XX and the IOu-COI'HPOUIICIS of formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydro-halogenation steps of this reaction sequence, it is sometimes preferable to convert the fl-compound of formula XX into the corresponding IDOL-compound of formula XIX. This conversion can be effected by treating a 10fl-desA-androstan-5- one or IOB-desA-pregnan-S-one of formula XX with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of formula XVIII to compounds of formulas XIX and XX can be effected without protection of any of the substituents which might be present at 0-16 or C-17. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of formula XVIII to compounds of formulas XIX and XX can be effected with protecting groups present on substituents in the C-16 or (3-17 position.

As stated above, the 10u-desA-androstan5-ones or 10w desA-pregnan-S-ones of formula XIX or the IOfl-desA- androstan-S-ones of l0l3-desA-pregnan-5-ones of formula XX can be converted via a two-step sequence of halogenation and dehydrohalogenation into the desired starting material desA-androst-9-en-5-one or desA-pregn-9-en-5-one of formulas XII, XV, and XVI.

In a preferred embodiment a 10a-desA-androstan-5-one or a IOa-desA-pregnan-S-Qne of formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation Halogenation of a compound of for- -mula XIX or a compound of formula XX yields a mixture of corresponding halogenated compounds including one of the formula r/NA Halli Lil H X XXIII wherein X and Z have the same meaning as above, and Hal is a halogen atom (preferably Br or Cl).

Dehydrohalogenation of a compound of formula XXIII then yields a desired starting material of formulas XII, XV and XVI. Keto groups exceptfor the S-keto group, may requireprotection prior to thehalogenation. In the case of compounds of formulas XIX andXX containing the C-l7 diliydroxyacetone sidechain, represented in formula V wherein R 'is hydroxy, this protection can be effected by formation of the 17a,20;20,2l-bis-rnethylene-i' Suitably effected by treatment with bromine at room temthe 20-oxo group.

perature or below, preferably at ice'temperature-or'beloyv. Suitably it is conducted :in an organic medium; forexample, an organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst. When effecting halogenation with sulfuryl chloride, it is suitable to use the same type of organic medium as when brominating; and suitable catalysts are, for example;- acetic acid, benzoyl peroxide, or the like. I

The subsequent dehydrohalogenation, of a compound of formula XX'III is preferably conducted under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate -(e.g. lithium carbonate) or an alkali metal halogenide (eg. a lithium halide)ri-in an organic solvent such as a di-lower alkyl-formarnide, or with an organic base such as collidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50 C. to about 150 C., preferably from about C. to about C.

Separation of the desired product desA-and'rost-9-an-5- one or desA-pregn-9-en-5-one. of formulas XII, and XVI can be effected by conventionalmeans. As indicated above the halogenation procedure may result in halogenated by-products in addition to the desired intermediateof formula XXIII. Accordingly, the separationfis preferably effected after first subjecting the reactionpmixtureto dehalogenating conditions in order to dehalogenate, the halogenated by-products formed by the ,halogenatiorijprocedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional, means, for example, by column chromatography, ,to yieldl'jthedesired compound of formulas XII, XV, XVI.,An exemp1a'ry dehalogenation means is treatment with zinc and sodium acetate in an acetic acid solution at an elevated temperature, for example, about 80 C. I l v In the case of compounds of formula XIX or XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect'such a halogen atom against dehalogenation prior to subjecting the compound of formula XIX or XX ,to the two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to'a keto group, is illustrated in a compound of formulaIV or V wherein -R or R is halogen. Thus, if lots-or. 10B- desA-pre'gnan- S-one of formula XIX or XX containing 3-..l7a-QO1 fl 2lhalo substituent is to be subjected to thehalogenationdehydrohalogenation sequence it is desirable to first effect protection of the 1711- or 2l-halosubstituent. Thi ""rotection can be effected, for example, byketali'z atio of As stated above, the desired desA-androst 9;en-5-ones or desA-pregn-9-en-5-ones starting materials canjalsolbe prepared from steroids of the 3-oxo-androstl-enie.or:3- oxo-l7f3-pregn-4-ene series containing an. ll-hydroxy s uh stituent. In one embodiment an 11 -hydroxy steroi formula 1 wherein X and Z havethe same meaning asr-abo've, is reacted with an acid or a reactive derivative "thereofto form a leaving group -in the l l-position.'By -reactive derivative is meant for example, a halide, e.g. a chloride,

an anhydride, or the like. Though either 11,8- or 1104- hydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the C-l6, C-l7, or C-2l position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the ll-position are inorganic acids such as phosphoric acid, organiccarboxylic acids such as anthraquinone fi-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methane-sulfonic acid and nitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of formula XXIV with a sulfonyloxy forming moiety, then a compound of formula XXIV having an lla-configuration should be used as a starting material. The above described esterification of ll-hydroxy steroid starting materials of formula XXIV yields compounds of the formula t 1 X XXV X XXVI wherein X, Z and LO have the same meaning as above.

The oxidative ring opening of the A-ring of a compound of formula XXV to a compound of formula XXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of formula XVII to a compound of formula XVIII. Pyrolysis of the so-formed compound of formula XXVI under the conditions described above for the pyrolysis of a compound of formula XVIII to compounds of the formulas XIX and XX directly yields the desired desA- androst-9-en-5-one or desA-pregn-9-en-5-one of formulas XII, XV, XVI. Thus, pyrolysis of a compound of for- "mula XXVI directly results in elimination of the leaving group in the ll-position as well as a splitting off of the residue of ring A attached to the 10-positiou. This procedure of starting from an ll-hydroxy steroid (preferably llu-hydroxy) of formula XXIV and proceeding through intermediates of formulas XXV and XXVI to compounds of formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of formula XXVI involves two separate chemical attacks; one being the elimination of the ll-leaving group and the other being the splitting olf of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, elfecting elimination of the leaving group of the compound of formulae XXVI. This elimination yields a A -seco acid of the formula Ha? H Z O X XXVIA wherein X and Z have the same meaning as above.

The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is efiected the A -seco acid product of formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of formula XXVI to compounds of formulas XH, XV and XVI.

After the above-described ll-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of formulas XV and XVI to isolate by forming the disemicarbazone of the pyrolysis product and then regenerating therefrom the desired 5,20-dione of formulas XV or XVI, or if the 20-oxo group has been protected, for example, by reduction to a 2 0- 'hydroxy moiety, by forming thhe semicarbazone at the 5- 19 toneor an l 1-hydroxy-3-0xo-3,5-seco-A norpregnan-3-oic a'cid 3,11'-lactone of the'fo'rmula i XXVII wherein X and Z have the same meaning as above.

Treatment of the 3,11-lactone of formula XXVII with an alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Without isolation, this salt can then be subjected to pyrolysis yielding a mixture of an 1l-hydroxy-lOa-desA-androstan-5-one and an ll-hydroxy-ltlfi-desA-androstan-S-one or a mixture of an 11- hydroxy-IOa-desA-pregnan-S-one and an ll-hydroxy-lOB- desA-pregnan-S-one, as illustrated below:

XXVII alkali metal salt XXVIII XXIX quence, it is suitable to utilize the Ion-compound of formula XXVIII. Conversion of the IOOt-COIIIPOUIld of formula XXIX to the 10,8-compound of formula XXVIII can be effected under the same conditions as described above for the conversion of the compound of formula XX to a compound of formula XIX.

In the next step of this reaction sequence, the ll-hydroxy compound of formula XXVIII or of formula XXIX can be subjected to esterification whereby to convert the ll-hydroxy group to a leaving group in the ll-position. This esterrfication can be effected with the same acids or acid derivatives and in the same manner as described above for the esterification of a compound of formula XXIV to va compound offorfmulaXXV. As in that, instance, it is also preferred in the present instance to form a mesoxy leaving group in the ll-position, though, of course, other leaving groups as described above are 'useful'for the in- ;stant purpose. There is thus obtaineda compound of the formula wherein X, Z and LO have the same meanings as above.

'Theleavinggroup can then' be eliminated from-the ll-position of a compound of formula'XXX resulting in a direct formation of a desA-androst-9' en-5-one or a desA pregn-9-en-5-one of formulae XIL'XV, XVI. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organicsolvent. Preferably, it is effected by heating, i.e. at a temperature'between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula )QIX with either an inorganic or organic base resultsv in the formation of the desired compound of formulae XII, XV,

XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (tag. a lower alkanoic acid) with an alkali metal or an an alkaline earth metal, for example, sodium acetate; potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethyl formamide', lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as 'dimethyl-formamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material; I

In another aspect, compounds of formula XXX can be prepared from compounds of the formula XXXA wherein X, Z and LO have the same meanings as above. The compounds of formula XXXA can be prepared from corresponding ll-hydroxy compounds by esteri-fication as described above for the preparation of compounds of formula XXV from compounds of formula XXIV. The compounds of formula XXX can be prepared from compounds of formula XXXA in the same manner that compounds of formula XXX are prepared from compounds of formula XXV, i.e. by oxidative ring opening of the A-ring of a compound of formula XXXA followed by elimination of the residue of the A-ring to yield a compound of formula XXX. The oxid-ative ring opening of the compounds of formula XXXA-can be performed by ozonolysis as described above for conversion of a compound of formula XXV to a compound of formula XXVI. Such ozonolysis of a compound of formula XXXA- yields a compound of the formula 1 v XXXB .wherein X, Z and LO have the same meaning as above. A compound of formula XXXB can then be converted to a compound of formula XXX; This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of acompound 'of formula XIXB to a compound of formula XIX- The compounds of formulae I-V" preparable by the 'rnethods of this invention are not 'only pharmaceu-tically useful compounds as described above, but also are'themselves useful as intermediates for other 9fl,l0oc-steroids;

for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce-unsaturation between C6 and -7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,6-difcyanobenzoquinone, according to known methods. Thus, for example, a 913,10a-progesterone of formula IV wherein X-is hydrogen or lower alkyl can be converted to a 9/3,l0a-pregna-4,6-dien-3,20-dione.

A further embodiment of this invention comprises the preparation of 9fi,10a-steroids of formulae I-V containing'an ll-hydroxy substituen-t. This can be effected by utilizing an 11 hydroxy 10a desA androstan-S-one or 11 hydroxy 10oz desA-pregnan-S-one of formula XXIX or an 1l-hydroxy-10,3-desA-androstan-5-one or 11- hydroxy-10/3-desA-pregnan-5-one of formula XXVIII as the starting materials. It is preferred in this embodiment to use the 1013-isomers of formula XXVIII as starting materials. As a first step in this the ll-hydroxy group of the compound of formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the so-obtained ll-esterified hydroxy compound when yields an ll-(esterified hydroxy)-desA- androst-9-en-5-one (i.e. a compound of formula XII containing an ll-esterified hydroxy moiety) or an ll-esterified hydroxy-desA-pregn-9-en-5-one (i.e. a compound of formulae XV-XVI containing an llm-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of formula XIX or XX to a compound of formula XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula XXXI XXXIA wherein R is hydrogen, fluoro, lower alkyl, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, 'benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityl- 'oxy, allyloxy or lower alkoxy-lower alkoxy; R is hydrogen, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, 'benzoyloxy, tetrahydropyranyloxy, benzyl- .oxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxylower alkoxy; R ishydrogen, lower alkyl, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; X' is a substituent in the 6-.position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, and

lower alkanoylthio or asubstituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower al-kylthio, lower alkanoylthio and halogen; E0 is lower alkanoyloxy, benzoyloxy or carboxyloweralkanoyloxy; R7 is hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, lower alkoxy, allyloxy or lower alkoxy-lower alkoxy; and R is hydrogen or, taken together with R 0x0 or lower alkylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di(loweralkyl) ketone, a cycloalkanone containing from 4 to 6 carbon atoms, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanal, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone or benzophenone; or R R R and R taken together form a bis-methylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di(loweralkyl)ketone, a cycloalkanone containing from 4 to 6 carbon atoms, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanal, a (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone, or benzophenone; yields an ll-esterified hydroxydesA-9B,10,3-androstan-5-one or ll-esterified hydroxydesA-918,10fl-pregnan-5-one, of the formula wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of formulae XII-XVI to a compound of formulae VII, X, XI. Also, compounds of formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing a 17,8-hydroxy, 17a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of formula XXXII, i.e. wherein E0 is hydroxy.

Condensation of the so-obtained compound of formula XXXII or the corresponding 17/8-hydroxy, 17u-lower alkenyl or lower alkynyl compound (i.e. a compound of formula VI containing a free or ll-esterified hydroxy group) then yields the desired end-product 9 8,10a-steroid of formulae I-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of formulae I-V from a compound of formulae VIXI. The so-obtained 9,8,10asteroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an ll-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the ll-hydroxy group can be oxidized by methods known per se to yield corresponding ll-oxo steroids analogous to compounds of formulas I-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees -centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, P.O. lBOX 989, Tallahassee, Fla. (cf. p. 1590, Merck Index, 7th edition, 1960). -200 mesh material was used. The moiety designated by tetrahydropyranyl- "23 oxy is tetrahydro-2-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at C. Throughout this application when compounds of the pregnane series are'referred to it should be understood 'that it is compounds of the l7 3-pregnane series that are being referred to, unless specifically indicatedto the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17B-series.

EXAMPLE 1 A solution of 3.2 g. of l7a-ethyltestosterone in50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at 70 (acetone-Dry Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of ml. of 30 percent hydrogen peroxide, left for 24 hours at 05. Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2N sodium carbonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline l7a-ethyl-l7fl-hydroxy-5- oxo 3,5 seco-A-norandrostan 3 oic acid was filtered, washed with water and dried. Upon being recrystallized from acetone, it melted at 196-197".

EXAMPLE 2 A solution of 1.5 g. of 17a-ethyl-l7fl-hydroxy-5-oxo- 3,5-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titrated with 2N sodium methoxide to the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17aethyl-17/3-hydroxy-5-oxo 3,5 seco A norandrostan-3- oic acid. 5 g. of sodium-phenylacetate was added to the residue, and the mixture pyrolyzed in vacuo 0.1 mm.)

.at 285+295, for 2.5 hours. The sublimate was dissolved in acetone, filtered and the filtrate concentrated in vacuo. The resultant syrupy residue was chromatographed on a 60 g. Florisil (adsorbent) column. The fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and gave 170: ethyl l7fl hydroxy-l0u-desA- androstan-S-one, mp. 94-95 after recrystallization from petroleum ether. The fractions eluted with 2 percent and 5 percent ethylacetate in benzene were combined and gave 17a ethyl l7fl-hydroxy-10,8-desA-androstan-5-one, m.p. 185-1855", after two recrystallizations from petroleum ether.

EXAMPLE 2a To a solution of 100 mg. of 17a-ethyl-l7fi-hydroxy-10B- desA-androstan-S-one in 10 ml. of absolute ethanol was added one equivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatography showed the product to be 17a-ethyl 17/8 hydroxy-10a-desA-androstan 5-one. It was obtained crystalline from petroleum ether-ether and melted at 89-95.

EXAMPLE 3 1.13 g. of 17a-ethyl-17fi-hydroxy-10a-desA-andrOstan-S- one was dissolved in 120 ml. of anhydrous ether (or 1.13 g. of lOfl-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed by the dropwise addition during five minutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml.-

of ether added,v shaken and separated. .The ether part was tion was heated at 100?. for-45;minutes;.=After cooling,- ,i t

was poured into one lither of ether, washed with-water, 1N hydrochloric acid, 2N, sodium carbonate, water, dried and evaporated. The residue was dissolvedin 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2g. of zinc powder added, and the so-formed mixture'heated 10 minutes at It was thenpoured into one-liter of ethylacetate and the resultant-solution washed with; satu rated sodium bicarbonate, then with water, dried; and evaporated. The residue'waschromatographed onlFlorisil (adsorbent) column. The fraction with benzene-and percent ethylacetate in benzene ga-ve regenerated starting material. Fractions with 1 and 2 percent ethylacetate in benzene gave 17a-ethyl-l7fl-hydroxy-desA-androst-9-en-5- one, which after sublimation (140 and 0.1 mm.,Hg vacuum), was obtained as a glass. [0411 -36.6;-(c.=1,

CHCl I EXAMPLE 4 A suspension of 262mg. of 5 percent rhodiumi'on alumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2N sodium hydroxide solution was prereduced (i.e. hydrogenated at room temperature and atmospheric pressure). To this was added a solution of 262 mg. of 17u-ethyl-l7 3-hydroxy-desA-androst-9-en-5- one in 15 ml. of 95 percent ethanol, and the mixture then hydrogenated at atmospheric pressureand room temperature. After one mole-equivalent of hydrogen was ab'so rbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo. Glacial acetic acid (1 ml.) was added to the residue, which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2N Na CO solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil (adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, which were followed by non-crystalline fractions. The non-crystalline fractions were dissolved in ml. of methylene chloride, and after the addition of 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirred overnight. The excess of chromic acid was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solution, followed by washing with 2N Na CO solution and then with water. It was then dried and evaporated in vacuo. The residue was dissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodium ethoxide, and left overnight. The next day, after addition of 0.5 ml. of glacial acetic acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2N Na CO solution, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gave crystalline 17a ethyl-17f3-hydroxy-desA-9fi,10,8-androstan-5-one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations, from ether, it melted at 142-144"; [ch 5 --11.65 [methaho], c.=l.2 45 percent].

EXAMPLE .5

To a solution of 132 mg. of '17a-e'thyl-17fi-hydroxydesA-9fi, l0B-a'ndrostan-5-one in 12.5--'ml.'of"absolute ethanol containing 34 mg. of sodium ethoxide, 015 m1: of

' 0.1 ml. of glacial acetic acid was added thereto" and-the 'resultingrnixture was then poured into 1 liter of ether.

The resultant ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo.

The residue was chromatographed on fluorescent silicaafter evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure A PLE 6 solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chloride was treated with ozone at .--70 until the solution became blue in color. Oxygen was then passed through and the solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100 ml. of glacial acetic acid, and after the addition of ml. of 30 percent hydrogen peroxide, left for 24 hours at 2 (in an ice box). The solution was then evaporated in vacuo, and the residue triturated with ether yielding crystals. Recrystallization from acetone yielded 1la-hydroxy-3,5-seco-A-norpregnane-5,20-dione-3-oic acid 3,11-lactone, mp. 253-- 256. [aJ +1933 (c.-=1, in chloroform).

EXAMPLE 7 A methanolic solution of 7.5 g. of 11a-hydroxy-3,5- seco A-nor-pregnane-5,20-dione-3-oic acid 3,1l-lactone was treated with one equivalent of ION sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the so-obtained sodium salt and the mixture pyrolyzed at 295 for two hours in vacuo.

'The crude sublimate was chromatographed on a silica-gel column and eluted with per cent ethylacetate in benzene. The amorphous solid 11a-hydroxy-10a-desA-pregnane-5,20-dione was first eluted from the column. IR- spectrum inchloroform: 3620 and 3600 cm? (-OH); 1706 cm. (carbonyl group). N-MR-spectrum in deuter- 'ochloroform: a doublet for l0a-CH at 73.5 and 80.5

c.p.s. downfield from TMS at 60 mc./ sec. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline llu-hydroxy-l0fi-desA-pregnane-5,20- dione which was recrystallized from methylene chloridepetroleum ether, mp. 150-152"; [a] +84.0 (c.=0.5 .in absolute ethanol).

EXAMPLE 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pryridine, there was added 100 mg. of 11ahydroxy-lOB-desA-pregnane-S,20-done. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water 100 ml.) and extracted with chloroform (3x 150 ml.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, IN hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from "ether, giving 1lu-hydroxy-10 3-desA-pregnane-5,20-dione 'methanesulfonate, m.p. 139-14(); [(11, +46 (c.=0.5

in absolute ethanol).

EXAMPLE 9 EXAMPLE 10 To a solution of 20 g. of lld-hydroxy-progesterone in 150 ml. of pyridine mantained at 0", there was added 6 ml. of methane-sulfonylchloride, and the reaction mixture allowed to stand overnight at 0. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give 1lm-mesyloXy-progesterone, m.p. 150-160; [M +145.6 (c. =1, chloroform). 1

EXAMPLE 1i A solution of 12 g. of 1la-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at -70 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture for five minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was then allowed to stand overnight at 2 (i.e., in the refrigerator), then evaporated to a volume of 75 ml. and diluted with ml. of benzene. The aqueous solution, obtained by extraction with 8 portions of 75 ml. 2N sodium carbonate followed by combining the aqueous extracts was acidified with cold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude lla-mesoxy-5,20- dioxo-3,5-seco-A-nor-pregnan-3-oic acid. After recrystallizing from acetone-petroleum ether, m.p. 152153; [(11 +47.9' (c.==l, chloroform).

EXAMPLE 12 A solution of 6 g. of 11u-mesoxy-5,20-dioXo-3,5-seco-A- norpregnan-3-oic acid in ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica-gel column (benzene eluant) gave crystalline desA-pregn-9-ene-5,20-dione; mp. 111-- 113 (after recrystallization from ether). +568 (0:0.25 percent in methanol).

EXAMPLE 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20 ml. of methanol maintained at 0", there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0. It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel column and the eluates with 5 percent ethyl acetate in benzene, after concentration gave crystalline ZOB-hydroxy-desA-pregn-9-en- 5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, mp. 122- 123; M1 33 (c.=0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of 20p- 27 hydroxy-desA-pregn-9-en one in 15, ml. ofv 9 -5 percent ethanol, and the reaction mixture-then hydrogenated at roomtemperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. [To the residue was added 1 m1. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2N aqueous sodium carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to f dryness in vacuo. -It yielded a colorless oil, which was chromatographed on'a silica-gel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was 20,B-hydroxy-IOa-desA-pregnan-S-one, mp. 107-108 after recrystallization from methylene chloride/petroleum ether. R.D. (in methanol); [M 25.3, [a].

89; [061350 [0C]35* [Ot]3oo 1165.

Further elution yielded 20/3-hydroxy-9fi,lOB-desA- 'pregnan-S-one as a colorless oil. R.D. (in methanol): [oz] EXAMPLE A suspension of 262 mg. of 5 percent'rhodium on alumina catalyst in a mixture of 2 ml. of 3N aqueous hydrochloric acid and 18 ml. 95 percent ethanol was hydrogenated at room temperature and atmospheric pressure. A solution of 262 mg. of B-hydroxy-desA-pregn- 9-en-5-one in 5 ml. of absolute ethanol was introduced ,into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated :by filtration, and the filtrate neutralized with 2N aqueous sodium hydroxide solution. An excess of 5 ml. of 2JN aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanol was then removed by evaporation at reduced pressure, and after addition of 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the elutant. The first fractions of the eluate yielded, upon concentration, 205- hydroxy-l0a-desA-pregnan-5-one. From the immediately subsequent fraction, 20fi-hydroxy-9fl, IOB-desA-pregnan- 5-one was obtained. Both products were identical with the same compounds obtained in Example 14.

EXAMPLE 16 20B-Hy-dr-oxy-9B,10et-pregn-4-en-3-one is prepared by condensation of 20fl-hydroxy-9fl, IOfl-desA-pregnan-S-one with methyl vinyl ketone according tothe procedure of Example 5. The product melts at 1765-1785"; [(11 143 (chloroform).

EXAMPLE 17 A medium is prepared of 20 g. of Edamine enzymatic digest of lactalbumin, 3 g. ofcorn steep liquor and 50 g.

of technical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain suspension of the steroid in the culture is incubated under' the same conditions of temperature and aerationfor an additional 24 hour period after which the beer and rnycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately toxy-l la-mesoxy-progesterone, according equal in'volume torthe rriyelium, extracted. twice, each the mixed extracts and beer filtrate, and thenwith 2 'ertions of methylene chloride, each portion being A the volume of the mixed extracts andbeer filtrate. The combined methylene chloride extracts are then washed with' 2 portions of a 2' percent aqueoussolutio'nof sodiurrr bicarbonate, each portion being /10 the volume of the combined methylene chloride extracts. The methylene chloride e'xtracts are then dried with about 35 g." of anhydrous sodium sulfate per liter of solvent, and 'thenffiltereda-The solvent is then removed from the filtrate by-distillation, and the residue is dissolved in a minimum of'me'thyle'ne chloride, filtered and the solvent evaporated from 'the'filtrate. The resulting crystals are thendried and washed five times, each time witha 5 ml. portion of ether per gram of crystal. The crystals are then recrystallized-from ether giving 170: acetoxy-l1ahydroxy-progesterone. 17a-acetoxy-lla-mesoxy-progesterone is prepared by treatment of 17a-acetoxy-1la-hydroxy-progesterone with methanesulfonyl chloride, according to the procedure of Example 10. i

EXAMPLE 18' 17a-Acetoxy 5,20 dioxo-llarmesoxy-A-nor,S-secopregnan-3-oic acid is prepared by ozonolysis of 17a-jaceto the procedure of Example 11. I

EXAMPLE 19 17a-Acetoxy desA pregn 9 ene 5,20-dione is prepared from 17a-acetoxy 5,20-dioxo-1la-mesoxy-A nor- 3,5-seco-pregnan-3-oic acid by conversion of the latter. to its sodium salt followed by pyrolysis, according to the procedure of Example 12. f j

EXAMPLE 20 l7a-Acetoxy 206 hydroxy desA pregn-9-en-5-one is prepared from 17a-acetoxy-desApregn-9'-en 5,20-dione by reduction and reoxidation according to the procedure of Example 13.

EXAMPL'E 21 17a-Acetoxy-20B-hydroxy 9,8,10 3 desA-pregnan-S- one is prepared from 17a-acetoxy 2073 hydroxy desA- pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15. 1

EXAMPLE 22 prepared by condensing 20,6 hydroxy 913,105 desA 17fl-Hydroxy 5 oxo 3,S-seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

. 29 EXAMPLE 25 17fl-Hydroxy lQa-desA androstan one and 17B- hydroxy-lOfi-desA-androstan 5 one are prepared from 17fl-hydroxy 5 oxo 3,5-seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, accordingto the procedure of Example 2.

EXAMPLE 26 17B Hydroxy desA androst-9-en-5-one is prepared from 17 3 hydroxy IOa-desA-androstan-S-one by bromination followed -by-dehydrobromination, according to the procedure of Example 3.

EXAMPLE 26a DesA-androst-9-ene-5,17-dione is prepared from 17(3- hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2 percent chromic acid solution in 90 percent acetic acid. The so-obtained desA androst-9-ene-5,l7- dione is recrystallized from cyclohexane and melts at 123- i Mt 123.5 (c. 0.1021, dioxane).

EXAMPLE 27 A solution of 236 mg. of 17B-hydroxy-desA-androst-9- en-5-one in 40 ml. 95 percent ethanol and 5.25 ml. 2N

aqueous sodium hydroxide solution was hydrogenated olysis, pyrolysis, bromination and dehydrobromination,

and reductionaccording to the methods of Examples 24, 25, 26 and 27 respectively, and melts at 118-1 19; [a];;. 28" (c'.=0.l03; dioxane).

EXAMPLE 28 A solution of 238 mg. of l7fi-hydroxy-9,3,10fl-desA- androstan-S-one, 1 ml. of ethylene glycol and catalytic amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and 17B-hydroxy-9BJOB-desA- androstan-S-one S-ethylene ketal was obtained from the residue by crystallization. M.P. 1151l6; [uh- 9 (c.'=0.0987; dioxane) EXAMPLE 29- To a solution of 282 mg. of 17fi-hydroxy-9p,10p-desA- androstan-S-one S-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic 'acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with 10 percent aqueous sodium hydrogen sulfite, 2 N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness.

Crystallization of the residue gave 9fi,10fl-desA-andro-;

stane-5,17-dione 5 monoethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic .amount of p-toluene sulfonic acid gives 9}8,l0fl-desA- androstane-5,17-dione which melts, after recrystallization from cyclohexane, at 775-78"; i+55 (c.-=0.107; dioxane). 'EXAMPLE '30 To a preformed solution of one mole equivalent of prop- 1'-inyl lithium in 100 ml. of anhydrous liquid ammonia 30 desA-androstane-S,17-dione S-mono-ethylen ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residuewas extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was'dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted inmethylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave 17a-(prop-1'-inyl) 17,8 hydroxy-913,105- desA-androstan-S-one.

EXAMPLE 31 17a-(prop-l-inyl)-l7B-hydroxy 95,10 androstan-4- en-3-one is prepared by condensing methyl vinyl ketone with 17 (prop-1'-inyl)-17p-hydroxy-9,3,IOB-desA-androstan-S-one according to the procedure of Example 5. The product melts at l64-l65.

EXAMPLE 32 To a stirred solution of one mole equivalent of 2- methyl-prop-Z-enyl magnesium bromide in ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9fl,10fl-desA-androstane-5,17-dione 5- mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an ice-salt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of p-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. From the residue 17a-(2'-methyl-prop-2'-enyl)17fl-hydroxy-9fi, 1018 desA androstan-S-one was obtained.

EXAMPLE 33 171x-(2'-methyl-prop-2'-enyl) 1719 hydroxy 95,100:- androst-4-en-3-one is prepared from 17a-(2'-methyl-prop- 2-enyl)-17B-hydroxy 96,10 8 desA androstan-S-one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The product melts at 106-108".

EXAMPLE 34 7 EXAMPLE 3S V16u-Acetoxy-20-ethylenedioxy 10a desA-pregnan-S- one and l6a-acetoxy-20-ethylenedioxy-lOfi-desA-pregnan- 5-one are prepared from 1 6a-acetoxy-ZO-ethylenedioxy-S- oxo-3,5-seco-A-norpregnan 3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with .aceticanhydride and pyridine. 2 2

' 'EXAMPLE 36 16a-Acetoxy 20 ethylenedioxy desA pregn-Q-en-S- one is prepared from lfia-acetoxy 20 ethylenedioxy- 10o: desA pregnan-S-one by bromination followed by Example 10.

1 EXAMPLE 38 h r65; Hydroxy; 20f ethylenedioxy 'f- 9,94%

4 en "3 one'is prepared bycondensi'ng l Ga acetoxy- 2O 'ethylenedioxy-de'sA- 9 6,105 pregnan 5 J one with methyl vinyl ketone according to the procedure of Example 5.

EXAMPLE 39 3/3 Hydroxy 16a methyl-pregn 5 en 20 one ethylene ketal is prepared by ketalization of 3 13 hydroxy- 16a methyl-pregn 5 en 20 one in benzene solution with ethylene glycol using p-toluenesulfonic acid as catalyst. Pyridine-chromic acid oxidation of the so-obtained 3B hydroxy 16a methyl-pregn 5 en 20 one ethylene ketal yields 16cc methyl 20 ethylenedioxypregn 4 en 3 one. 16a methyl 20 ethylenedioxy- 5 x0 3,5 seco-A-norpregnane 3 oic acid is prepared by ozonolysis of 160; methyl 20 ethylene-dioxypregn-4-en-3-one according to the procedure of Example l.

EXAMPLE 40 16a Methyl 20 ethylenedioxy 10a desA-pregnanone and 16a, methyl 20 ethylenedioxy 1013- desA-pregnan-S-one are prepared from 160: methyl 20- ethylenedioxy 5 oxo 3,5 seco-A-norpregnan 3- oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 41 16a Methyl 20 ethylenedioxy-desA-pregn 9 en- 5 one is prepared from 160: methyl 20 ethylenedioxy cc desA-pregnan 5 one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42 16a Methyl ethylenedioxy 95,1013 desA- pregnan 5 one is prepared from 16 methyl 20- ethylenedioxy-desA-pregn 9 en 5 one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

EXAMPLE 43 160: Methyl 20 ethylenedioxy 96,100: pregn- 4 en 3 one is prepared by condensing 160a methyl- 2O ethylenedioxy 9,6,10 8 desA-pregnan 5 one with methyl vinyl ketone, according to the procedure of Example 5. EXAMPLE 44 21 Acetoxy 11a hydroxy 20 ethylenedioxypregn 4 en 3 one is prepared by microbiological treatment of 21 acetoxy 20 ethylenedioxy-pregn 4- en-3- one, according to the procedure of Example 17. 21- Acetoxy--11 mesoxy 20 ethylenedioxy-pregn 4- en-3-one is prepared by treatment of ZI-ac'etoxy-lla-hydroxy 20 ethylenedioxy-pregn 4 ene 3 onewith r'rie'thanesulfo'nylchloride, accbrding to the procedure of EXAMPLE 45 r 21 Acetoxy 11a mesoxy 20 ethylenedioxy 5- oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 21 7 acetoxy 11a mesoxy 20 ethylenedioxy-pregn-4-en-3 one, according to the procedure of Example 11'. l J

, v. .10 pre'gn- 2 EXAMPLE 4 p 21 Acetox y 20 ethylenedioxy-desA pregn-9-en-5- yer'si n 'of the latter to its" spdiurn salt followed by pyrolysisgaccording to itheiprocedure of Example 12, except that the crude product is'r'eacetylated' by treatment with acetic anhydride/pynidi'ne. prior to its being workedup.v t a y v '7 v EX AIS lPLE.47 H 21 Acetoxy. 20 vethylenedioxy-:9;8,10 8 -"desA- pregnan 5 one is prepared from 21- acetoxy 2Q- ethylenedioxy-desA-pregn 9 en 5 one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedureof Example 15.

EXAMPLE 4s 21 Hydroxy 20- ethylenedioxy 919,10 pregn- 4 en 3 one isprepared'from 21 acetoxy 20- ethylenedioxy 9,8,10 3- desA-pregnan 5 one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 22. I I

EXAMPLE 49 11a Mesoxy 16a,1.7ot isopropylidenedioxyprogesterone is prepared by treatment-of 11a hydroxy- 16a,l7a isopropylidene'dioxy-progesterone with methane sulfonyl chloride, according to the procedure, of Example 10.

EXAMPLE 50 5,20 dioxo 11a mesoxy 16a,17u isopropylidenedioxy 3,5 seco-A-norpregnan -'3 oic acid is prepared by ozonolysis of 11oz mesoxy 16a,17a isopropylidenedioxy-progesterone, according to the procedure of Example 11. I

EXAMPLE 5 20,8 Hydroxy :,170: isopropylidenedioxy-desA- pregn 9 en 5 one is prepared from l6a,17a "isopropylidenedioxy-desA-pregn 9 ene 5,20 dione by reduction and reoxidation, according to the procedure of Example 13.

EXAMPLE 53 205 Hydroxy 16,17u r' isopropylidene'dioxy 913,10 desA-pregnan-S-one is'prepared from 205 '-.hydroxy 160a, a isopropylidenedioxy-desA-pregn 9 en 5 one by hydrogenation according to the. procedure of Example 14.

EXAMPLE 54 7205 Hydroxy- 16ec,17a isopropylidenedioxy 7 913,100:- pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 205 hydroxy 16a,-17w isopropylidenedioxy-desA 98,103- pregnan e 5 one according to the procedure of Example 5 1 1 E AMPLE 55 7a,17ct dimethyl 17B hydroxy 5 oxo 3,5 seco- A-norandrOstan-S-oic acid .is prepared fr0m'7a,l70c-'dimethyl-testosterone by ozonolysis of the latter, according to the procedure of Example 1.

EXAMPLE 56 7a,17a-dimethyl-17 3-hydroxy lOa desA-androstan- 5- one and 796,170t-dl1'116thY1 17,13-hydroxy-IOfl-desA-androstan5 one are prepared from 'l a,l7a-dimethyl-'l7 9-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid by com EXAMPLE 57 7u,17a-dimethyl 17/3 hydroxy-desA-androst-9-en-5- one is prepared from 7a,17a-dim6thYl-17fi-hydIOXy-10w desA-androstan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 8 I 7a,17o; -dimethyl 17,8 hydroxy desA-9,8,10;8-androst-an-S-one is prepared from 7u,l7u-dimethyl-l7fi-hydroxydesA-androst-9-en-5-one by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

EXAMPLE 5 9 7a,17u-dimethyl 95,100: tetosterone is prepared from 7a,17 x-dimethyl 17/3 hydroxy-desA-9B,lOfi-androstan- 5-one by condensing the latter with methyl vinyl 'ketone, according to the procedure of Example 5.

EXAMPLE 60 11a-Mesoxy-l7a-methyl-progesterone is prepared from 1la-hydroxy-17a-methyl-progesterone by treatment of the latter with methane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 61 11a-mesoxy-l7u-methyl-5,20-dioxo 3,5 seco-A-norpregnan-3-oic acid is prepared from 11a-mesoxy-17umethyl-progesterone by ozonolysis of the latter, according to the procedure of Example 11.

EXAMPLE 62 EXAMPLE 63 20,6-Hydroxy 17cc methyl-desA-pregn-9-en-5-one is prepared from 17a-methyl-desA-pregn-9-en-5,20-dione according to the procedure of Example 13.

EXAMPLE 64 20,8-Hydroxy-l7rx-methyl 9,19,10,63 desA-pregnan-S-one is prepared from 17a-methyl-20 8-hydroxy-desA-pregnan- 9-ene-5-one according to the procedure of Example 15.

EXAMPLE 65 ZOB-Hydroxy 17oz methyl-9 8,10u-pregn-4-en-3-0ne is prepared by condensing l7a-methyl-20fi-hydroxy-9 3,10,8- desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 4.

EXAMPLE 66 A solution of 12.8 g. of l7a-methyltestosterone in 200 ml. of methylene chloride and 100 ml. of ethyl acetate was ozonized for 1 hour and 5 minutes at 70 (acetone- Dry Ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 400 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at.0. It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material 17B-hydroxy-17amethyl-5-oxo-3,S-seco-A-nonandrostan-3-oic acid. After 34 recrystallization from acetone-hexane, it melted at 195- 7", ]D =9.8 (c. =1.0 in chloroform).

EXAMPLE 67 A solution of 10 g. of l7/3-hydroxy-l7a-methyl-5-oxo- 3,5-seco-A-nor-androstan-3-oic acid in 250' ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2N sodium carbonate solution, and again with water, dried and evaporated. This gave a sirupy residue, which by thin layer chromatograms and infrared spectra consisted of l7 3-hydroxy-l7a-methyl-loa-desA-androstan 5 one as the major and 17B-hydroxy-17u-methyl-10fl-desA-androstan-S-one as the minor product.

Three additional pyrolyses were performed as described above, and the combined products so-obtained was chro matographed on a 850 g. silica gel column, using 5% ethylacetate in benzene as the eluent. This chromatography yielded 17/3-hydroxy-17a-methyl-IOa-desA-androstan 5- one, which after recrystallization from petroleum ether melted at 96-97 [a] =28.2 (c.=0.5 in chloroform). Further eluates of the column gave product, 17,8-hydroxy-17a-methyl-IOfi-desA-androstan-S-one which, when recrystallized from ether, melted at -167", [a] -19.8 (c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of 17 8-hydroxy- 17a methyl-IOa-desA-andrOstan-S-One and l7/3-hydroxymethyl-IOB-desA-androstan-S-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml. of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of 17fi-hydroxy-17a-methyl-10a-desA-androstan-5-one.

EXAMPLE 68 To a solution of 11.2 g. of 17B-hydroxy-17u-methyl- IOa-desA-androstan-S-one in 1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disappearance of excess bromine. After bromination was complete, 53 ml. of 10% sodium hydrogen sulfite solution and 53 ml. of aqueous 2N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was then separated, washed with water, dried, and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100 for 45 minutes. After cooling, 2 liters of ether were added and the ethersolution washed with water, 1N hydrochloric acid, and then again with water, dried and evaporated/The residue was dissolved in 200 ml. of glacial acetic acid, 12.6 g. of sodium acetate and 12.-6 g. of zinc powder were added and the mixture heated for ten minutes at 80". After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethyleacetate, and washed with saturated sodium bicarbonate solution, then with water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first '17/8-hydroxy-l7a-methyl-IOa-desA-andrOstan-S-One, followed by 17,3 hydroxy-17a-methyl-dcsA-androst-9-en-5-one. After EXAMPLE 69 A suspension of 1.25 g. of rhodium on alumina catalyst in a mixture of 130 ml. of 95% methanol and 26 ml. of 2N sodium hydroxide was prereduced. To this was then added a solution of 1.25 g. of 17fi-hydroxy-17amethyl-desA-androst-9-en-5-one in 75 ml. of 95% ethanol. and then the mixture was hydrogenated at atmospheric pressure and room temperature. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was removed by filtration, and the filtrate evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the so-formed mixture then dissolved in 2 liters of ether, and the resultant cloudy solution was washed with water, then dried and evaporated. The residue was dissolved in 50 ml. of methylene chloride and oxidized with 5 ml. of 2% chromic acid in 90% acetic acid until green color of reaction mixture. After then being washed with sodium hydrogen sulfite solution 2N sodium carbonate solution and water, the reaction mixture was dried over sodium sulfate and evaporated. The residue was chromatographed very slowly on a 50 g. silica gel column, with 5% ethylacetate in benzene, and followed with thin layer chromatography. First, 17fl-hydroxy 17a methyl-9a,10a-desA-androstan-5-one was eluted. After a minor amount of mixed material, 17,3-hydroxy 17oz methyl-9,8,IO/E-desA-androstan-S-one was eluted. After recrystallization from ether-petroleum ether, it melted at 94-96".

EXAMPLE 7O 17a-Methyl-9/8,IDOL-testosterone is prepared from 170cmethyl-17fl-hydroxy-desA-9 8,IO/R-androstan-S-one by condensation of the latter with methyl vinyl ketone, according to the procedure of Example 5. The product melts at 128- 129.

EXAMPLE 71 A solution of 6 g. of 11a,20B-diacetoxy-pregn-4-en-3- one in 100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at -70. After methylene chloride was removed by distillation in vacuo, the residual solution was diluted to 100 ml. with ethylacetate. To this 5 ml. of 30 percent hydrogen peroxide was added and left overnight at room temperature. The reaction mixture was concentrated to dryness in vacuo, the residue taken up in 1 liter of ether, and the resulting solution extracted times with 50 ml. portions of 2N aqueous sodium carbonate. The carbonate extract was then acidified with icecold concentrated hydrochloric acid. The precipitated product was separated by filtration, and crystallized to give 110;,20/3 diacetoxy-S-oxo-3,5-seco-A-nor-pregnan-3- oic acid.

EXAMPLE 72 A methanolic solution of 5 g. of 11a,20/8-diacetoxy-5- oxo 3,5-seco-A-nor-pregnan-3-oic acid was treated with one-half mole equivalent of sodium carbonate, and evaporated to dryness in vacuo. Potassium acetate (5 g.) was added to the residue which was then pyrolyzed at 295 and 0.02 mm. The sublimate was chromatographed on a silica-gel column to give 11oc,20fl diacetoxy-IOB-desA- pregnan-S-one.

EXAMPLE 73 Bromination and dehydrobromination starting with 110:, 20,3 diacetoxy-IOB-desA-pregnan-S-one according to the procedure of Example 3, gave 11a,20p-diacetoxy-desA pregn-9-en-5-one. 1 EXAMPLE 74 36 EXAMPLE 7s 11a,20fl-Diacetoxy-9fi,IOfl-desA-pregnan-S-one was hydrolyzed in methanol solution with one mole equivalent of potassium carbonate to give 11u,20p-dihydroxy-9p,10fidesA-pregnan-S-one.

EXAMPLE 76 Condensation of 110L305 dihydroxy 918,105 desA- pregnan5-one with methyl vinyl ketone according to the procedure of Example 5 gave lla,20fl-dihydroxy-9/3,l0apregn-4-en-3-one.

EXAMPLE 77 A solution of 3 g. of 17a-ethyl-17fi-hydroxy-androsta- 1,4-dien-3-one in ml. of methylene chloride and 25 ml. of ethyl acetate was ozonized at 70 till it became blue. After evaporation to dryness, the residue was dissolved in ml. of glacial acetic acid containing 5 ml. of 30 percent hydrogen peroxide, and set at room temperature for '2 days. The reaction mixture was concentrated to dryness and the residue dissolved in one liter of ether. The ether solution was then extracted 10 times with 25 ml. portions of aqueous 2N sodium carbonate solution, and 'the carbonate extracts were acidified with ice cold concentrated hydrochloric acid. The non-crystalline precipitate containing 17a-ethyl-17/i-hydroxy-l0aoarboxy-desA-androstan-S-one was separated by filtration and dried, then dissolved in ml. of absolute ethanol, and after addition of- 9 ml. of aqueous 2N sodium hydroxide, boiled for 1 hr. The reaction mixture was concentrated in vacuo to a small volume, and diluted with 1750 ml. of ether. The ether solution was washed with Water, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was crystallized from etherpetroleum ether, to give l7a-ethyl-17B-hydroxy-l0=a-desA- androstan-S-one, m.p. 8990.

EXAMPLE 78 3( l75-hydroxy-5-oxo-3,5 seco A nor androstan- 17a-yl-3-oic acid)-propionic acid lactone is prepared by ozonolysis of 3-'(3-oxo=l7fl-hydroxy-andros -4-en-17a-yl)- propionic acid lactone, according to the procedure of Example 1.

EXAMPLE 79 EXAMPLE 8O 3-(17,6-hydroxy-5-oxo-desA androst 9 en 17a yl)- propionic acid lactone is prepared from 3-(l7 8-hydroxy- 5-oxo-lOa-desA-andrOstan-17a-yl)-propionic acid lactone by 'bromin ation followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 81 3-( 17 fi-hydroxy-5-ox-o-9fl, 10fl-desA-andros-tan-l7 a yl) propionic acid lactone is prepared from 3-(l7fl-hydroxy- 5-oxo-desA-androst-9-en-17a-yl) propionic acid lactone by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

EXAMPLE 82 3 (17B-hydroxy-3-oxo-9B,l0a-androst-4-en a yl)- propionic acid lactone is prepared by condensing 3- (17;8- hydroxy-5-oxo-9l3,10,8-desA androstan 17a yl) propionic acid lactone with methyl vinyl ketone, according to the procedure Of Example 5,

37 EXAMPLE 83 17a,20;20,21 bis methylened-ioxy 11a mesyloxypregn-4-en-3-one is prepared by treatment of 17u,20;20, 2l-bis-methylenedioxy-11a-hydroxy-pregn-4 en 3 one with methanesu'lfonyl chloride according to the procedure of Example 10.

'EXAMPLE 84 17a,20;20,2l-bis-methylenedioxy 11a mesyloxy 5- oxo-3,S-seco-A-norpregnane 3 oic acid is prepared by ozonlysis of 17a,20;20,2l-bis-methylenedioxy llu-mesyloxy-pregn-4-ene-3-one according to the procedure of Example 11.

EXAMPLE 85 17 z,-20;20,2l-bis-methylenedioxy-desA pregn 9 en- S-one is prepared from 17a,20;20,2l-bis-methylenedioxy- 11rx-mesyloxy-5-oxo-3,S-seco-A-norpregnan 3 oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example '12.

EXAMPLE 8 6 17a,20;20,2l-bis-methylenedioxy 918,103 desA pregnan-S-one is prepared from 17a,20;20,21-bis methylenedioxy-desA-pregn-9 en 5 one by hydrogenation in the presence of a rhodium catalyst according to the procedure of Example 14.

EXAMPLE 87 17a,20;20,21 bis-methylenedioxy-95,IOa-pregn 4 en- 3-one -is prepared by condensing methylvinyl ketone with 17a,20;20,21-bis-methylenedioxy-9fi,10$ desA pregnan- 5-one, according to the procedure of Example 5.

EXAMPLE 88 20B-hydroXy-9 8,IOa-pregna-lA-d ien 3 one was prepared by condensation of 20fl-hydroxy-9/3,IOB-desA-pregnan-S-one with 1 equivalent of methyl ethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

EXAMPLE 89 One ml. of Jones reagent (0.004 mole CrO is added to 200 mg. of 17fl-hydroxy-9BJOB-desA androstan 5- one in 20 ml. of acetone at The mixture is then left for minutes at room temperature, and 5 ml. of ethanol then added. The resulting suspension is evaporated to dryness in vacuo, water is'added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which crystallizes upon the addition of a small portion of petroleum ether. The so-obtained crystals of 95,10,6-desA- androstane-5,17-dione melt, after recrystallization from cyclohexane, 'at 775-7 8 li n +55 (c.=0.107, dioxane); R.D. in dioxane (c.=0.107%): in mu ual-value in degrees); 550 (+70); 400 (+297); 350 (+798); 320 (+2968) maX.', 300 (+467); 299 (0); 290 (1890).

EXAMPLE 90 l ltiii 38 (c.=0.103%, dioxane); R.-D. in dioxane (c.=0.103%): A in mp. ([a]-valuc in 400 (-30); 356 -(0); 350 (+10); 313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (O); 280 (--652).

EXAMPLE 91 A solution of 250 mg. of 17,8-acetoxy-9/3,IOfl-desA- androst-an-S-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide is refluxed for 60 minutes. The resulting mixture is evaporated to dryness in vacuo, water added to the residue and the suspension extracted with ether. The ether phase is Washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of 170- hydroxy 95,105 desA-androstan-S-one which upon being recrystallized from ethylacetate melt at 1445- 145;

M28 5 (c.=0.103, dioxane), R.'D. in dioxane (c.=0.103); A in m ([a]-value in 400 (-7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492) min.; 305 (+504) max.; 300 (+324); 293 (0); 290'(-202).

EXAMPLE 92 A solution of 10 g. of 1lp-formyloxy-androsta-1,4- diene-3,l7-dione in ml. of acetic acid was ozonized at 0 until thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml. of water and the mixture was then heated to 100 for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated sodium bicarbonate solution. The undissolved material was extracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The eluates were concentrated and gave, an addition of hexane, llfl-formyloxy 106 desA-androstane-S,17-dione, m.p. 117117.5 (recrystallized from acetone-cyclohexane), [a] =93 (dioxane).

EXAMPLE 93 By hydrolysis of 11fi-formyloxy-E-desA-androstane-5, 17-dione in 2% methanolic potassium hydroxide there is obtained 11,8 hydroxy 10E desA-androstan-5,17- dione, which melts at 154; [a] +=96 (dioxane).

EXAMPLE 9'4 250 mg. of 1l e-hydroxy-10desA-androstane-5,17- dione and 250 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benzene were refluxed in a nitrogen atmosphere for 6 hours. The reaction mixture was then washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was then chromatographed over silic'agel (5 g.) in dichloromethane. Triturating the residue obtained from the first 250 ml. eluted, yielded crystals of desA-androst-9-ene-5,17-dione, which upon recrystallization from cyclohexane melted at 123- 123.5".

EXAMPLE 95 The compound, 1lfl-formyloxy-S,17-dioxo-3,5-seco-A- norandrostan-3-oic acid is prepared from llB-formyloxyandrost-4-ene-3,1'7-dione by ozonolysis according to the procedure of Example '11. The so-obtained product melts at 220-221 '[a] 107 (dioxane).

EXAMPLE 96' 3.7 g. of the sodium salt of 11;3-formyloxy-5,17-dioxo 3,5-seco-A-nor-androstan-3-oic acid and 12 g. of sodium phenylacetate are fused together in vacuo (0.1 Torr). When the bath temperature reaches 220 the molten mass begins to decompose. The bath is then heated further (within 30 minutes) to a temperature of 290. Once this temperature has been reached the mixture is left for another 10 minutes at the initial pressure of 0.1 Torr. The distilled material is then chromatographed over 30 g. of aluminum oxide (activity grade 3). Elution with a total of 200 ml. of petroleum ether-benzene -(2:1), followed by evaporation of the solvent and tri-turation of the residue in the presence of of petroleum ether, yields desA-androst-9-ene-5,l7-dione which upon recrystallization from cyclohexane melts at 123-1235"; [a] +83 (c.=0.1021, dioxane).

EXAMPLE 97 20,8 Ace-toxy--oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of 20fi-acetoxy-pregn-4-en-3- one according to the procedure of Example 1.

EXAMPLE 98 A solution of 15.15 g. of 20B-aotoxy-5-oxo-3,5-seco- A-nor-pregnan-S-oic acid in 250 ml. of 75% methanol containing g. of potassium hydroxide was refluxed for 2 hours. The methanol was then removed in vacuo and the residue was dissolved in 100 ml. of water. The solution was chilled to 0 and acidified to Congo red by the addition of hydrochloric acid. There was thus obtained 20B hydroxy 5 oxo 3,5 seco-A-nor-pregnan- 3-oic acid, m.p. 181182, [a] =l3 (dioaxne).

A solution of 4.7 g. of 20,8-hydroxy-5-oxo-3,5-seco-A- nor-pregnan-3-oic acid in 100 ml. of methanol was neutralized with 1N sodium methylate solution against phenolphthaleine. The solution was then evaporated and the residue, consisting of 20 3-hydroxy-5-oxo-3,5-seco-A- nor-pregnan-3-oic acid sodium salt, was refluxed with 100 ml. of quinoline for 8 hours. The cooled mixture was poured on a mixture of 150 g. of ice and 100 ml. concentrated hydrochloric acid and extracted with ether. The ether extract was worked up and the oily residue was chromatographed on silica gel. Elution with methylene chloride gave 10a-desA-pregn'ane-5,20-dione, mp. 126-127 (crystallized from isopropyl ether), [a] 82 (dioxane). Elution with methylene chloride containing 1% acetone gave ZOB-hydroxy-IOu-desA-pregnan- 5-one, m.p. 104-1045 (crystallized from ether-hexane), [a] =1O (dioxane). The fractions obtained with methylene chloride containing 510% acetone were evaporated and the oily residue was dissolved in 40 ml. of acetone. The solution was treated with 3 ml. of Jones reagent (0.004 mole Cr0 at -10 and kept at the same temperature for 10 minutes. After the addition of 5 ml. of methanol, the solution was evaporated and the residue was diluted with water and extracted with ether. The ether extract was worked up and gave IOa-desA-pregnane-5,20-dione.

EXAMPIJE 99 203 hydroxy-desA-pregn-9-en-5-one is prepared from 20,8-hydroxy-10a-desA-pregnan-5-one by bromination followed by dehydrobromination, according to the procedure of Example 3. The so-obtained product, after recrystallization from methylene chloride-petroleum ether, melts at 122-123".

EXAMPLE 100 5,20-dioxo-3,S-seco-A-nor-pregnan 3 oic acid is prepared by ozonolysis of progesterone according to the procedure of Example 1.

EXAMPLE 10 1 10a-desA-pregna-5,20-dione and 10,8 desA pregnan- 5,20-dione are prepared from 5,20-dioxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 102 The compound, desA-pregn-9-ene 5,20 dione is prepared from 10a-desA-pregna-5,20-dione by bromination followed by dehydrobromination according to the procet 40 dure of Example 3. The so-obtained product, after recrystallization from ether, melts at 111-113.

EXAMPLE 103 15 ml. of 0.8% potassium permanganate solution was added to a mixture of 11 g. of ZOB-tetrahydropyranyloxypregn-4-en-3-one, 500 ml. of an azeotropic mixture of tertiary butanol and water, 7 g. of potassium carbonate, 20 ml. of water and 120 ml. of 7% sodium metaperiodate solution with vigorous stirring at room temperature. 250 ml. of 7% sodium metaperiodate and 20 ml. of 0.8% potassium permanganate solution were then simultaneous ly added within 15 minutes. To the so-obtained suspension, 220 ml. of 7% sodium metaperiodate solution and, in order to keep the mixture violet in color, 15 ml. of 0.8% potassium permanganate solution were then added in the course of 30 minutes. The mixture was then stirred for minutes, filtered over a filter aid (Hyfio) and the residue was washed with ml. of tert. butanol-water azeotrope. The filtrate was evaporated in vacuo at 50 and the residue diluted with 150 ml. of water. The solution was acidified with cold 20% hydrochloric acid to Congo red, and the resultant oily material taken up in 150 ml. of methylene chloride. The organic extract was washed with water, dried and evaporated and the residue was purified by filtration over silica gel using methylene chloride and methylene chloride containing 12% ethanol as the elution agents. There was thus obtained 20,8-tetrahydropyranyloxy-S-oxo-3,5-seco-A-nor-pregnan-3-oic acid as a viscous oil.

EXAMPLE 104 To a solution of 35.8 g. of a mixture of 20aand 2013- hydroxy-pregn-4-en-3-one in 500 ml. of anhydrous benzene, there were added 75 ml. of 1% p-toluenesulfonic acid in benzene and then 35 ml. of dihydropyran. The reaction mixture was allowed to stand at room temperature for 16 hours, washed with 2% aqueous sodium bicarbonate and water, dried and concentrated in vacuo at 11 mm. Hg and 80. The residue consisting of 20aand 20,8-tetrahydropyranyloxy-pregn-4-en-3-one was dissolved in 2 liters of tert. butanol-water azeotrope followed by the addition of a solution of 33 g. of potassium carbonate in 80 ml. of water and 620 ml. of 7% aqueous sodium metaperiodate solution. To the reaction mixture there was first added with vigorous stirring at room temperature, 75 ml. of 0.8% potassium permanganate and thereafter simultaneously within 30 minutes 1350 ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8% potassium permanganate solution. Another 1080 ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8% potassium permanganate solution were then added within 45 vminutes. The reaction mixture was then stirred for 1 hour, filtered over a filter aid (Hyfio) and the residue was washed with 250 ml. of tert. butanol-water azeotrope. The filtrate was evaporated, the residue taken up in 800 ml. of water and filtered. The alkaline filtrate was chilled to 0", acidified with cold 20% hydrochloric acid and extracted with methylene chloride. After working up, the extract afforded a mixture of ZOocand 20/3-tetrahydropyranyloxy- 5-0xo-3,S-seco-A-nor-pregnan-3-oic acid as a viscous oil. This oil was dissolved in 300 ml. of methanol and neu tralized with 1N lithium methylate. The solution was evaporated to dryness in vacuo. The oily residue was dissolved in 300 ml. of benzene, evaporated again and dried at 11 mm. Hg and 100 for 2 hours. There was obtained a mixture of the lithium salts of 201xand ZOB-tetrahydropyranyloxy-S-oxo-3,S-seco-A-nor-pregnan-3-oic acid as an amorphous powder.

EXAMPLE 105 A solution of 9 g. of 20B-tetrahydropyranyloxy-S-oxo- 3,5-seco-A-nor-pregnan-3-oic acid in 100 ml. of methanol was neutralized with 1N lithium methylate solution against phenolphthaleine, followed by evaporation in vacuo to dryness. The so-obtained residue was taken up 

